Favipiravir inhibits acetaminophen sulfate formation but minimally affects systemic pharmacokinetics of acetaminophen

Yanli Zhao, Jerold S Harmatz, Carol R Epstein, Yukako Nakagawa, Chie Kurosaki, Tetsuro Nakamura, Takumi Kadota, Dennis Giesing, Michael H Court, David J Greenblatt, Yanli Zhao, Jerold S Harmatz, Carol R Epstein, Yukako Nakagawa, Chie Kurosaki, Tetsuro Nakamura, Takumi Kadota, Dennis Giesing, Michael H Court, David J Greenblatt

Abstract

Aims: The antiviral agent favipiravir is likely to be co-prescribed with acetaminophen (paracetamol). The present study evaluated the possiblility of a pharmacokinetic interaction between favipiravir and acetaminophen, in vitro and in vivo.

Methods: The effect of favipivir on the transformation of acetaminophen to its glucuronide and sulfate metabolites was studied using a pooled human hepatic S9 fraction in vitro. The effect of acute and extended adminstration of favipiravir on the pharmacokinetics of acetaminophen and metabolites was evaluated in human volunteers.

Results: Favipiravir inhibited the in vitro formation of acetaminophen sulfate, but not acetaminophen glucuronide. In human volunteers, both acute (1 day) and extended (6 days) administration of favipiravir slightly but significantly increased (by about 20 %) systemic exposure to acetaminophen (total AUC), whereas Cmax was not significantly changed. AUC for acetaminophen glucuronide was increased by 23 to 35 % above control by favipiravir, while AUC for acetaminophen sulfate was reduced by about 20 % compared to control. Urinary excretion of acetaminophen sulfate was likewise reduced to 44 to 65 % of control values during favipiravir co-administration, while excretion of acetaminophen glucuronide increased to 17 to 32 % above control.

Conclusion: Favipiravir inhibits acetaminophen sulfate formation in vitro and in vivo. However the increase in systemic exposure to acetaminophen due to favipiravir co-administration, though statistically significant, is small in magnitude and unlikely to be of clinical importance.

Keywords: acetaminophen; acetaminophen glucuronide; acetaminophen sulfate; drug interactions; favipiravir; paracetamol.

© 2015 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.

Figures

Figure 1
Figure 1
Inhibition curve for favipiravir vs. acetaminophen metabolite formation. Acetaminophen (2m m) and favipiravir were incubated with pooled human hepatic S9 fractions for 15 min. The reaction was stopped by adding acetonitrile. Acetaminophen and its metabolites were detected by LC/MS with electrospray ionization (ESI) negative and multiple reaction monitoring (MRM) mode. The 50% inhibition concentration (IC50) vs. acetaminophen sulfate formation was determined by non-linear regression. , Acetaminophen-sulfate; , Acetaminophen-glucuronide
Figure 2
Figure 2
Mean (±SE) plasma concentration of acetaminophen and metabolites at corresponding times for the 3 study days. Linear concentration axes are on the left, and logarithmic concentration axes are on the , day 1; , day 2; , day 6
Figure 3
Figure 3
Mean (±SE) urinary excretion of acetaminophen glucuronide (A) and acetaminophen sulfate (B). Excretion values are expressed as percent of the administered dose. , day 1; , day 2; , day 6

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